Tacrolimus Enhances the Potency of Posaconazole Against Rhizopus oryzae In Vitro and in an Experimental Model of Mucormycosis

Lewis, Russell E.; Ben‐Ami, Ronen; Best, Leyla; Albert, Nathaniel D.; Walsh, Thomas J.; Kontoyiannis, Dimitrios P.

doi:10.1093/infdis/jis767

Cited by 60 publications

(58 citation statements)

References 41 publications

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“…The calcineurin inhibitors FK506 and cyclosporine A synergistically inhibit the growth of Mucorales in combination with other antifungal drugs (Dannaoui et al 2009;Narreddy et al 2010;Thakur and Revankar 2011). Efficacious outcomes were observed for combination therapy with posaconazole and FK506 in both Drosophila and murine cutaneous mucormycosis model systems (Lewis et al 2013). Another study found that FK506 treatment enforces M. circinelloides to grow as its less virulent yeast form, rather than its invasive hyphal form (Lee et al 2013).…”

Section: Iron Chelation Therapy and Other Novel Approachesmentioning

confidence: 99%

Human Fungal Pathogens of Mucorales and Entomophthorales

Mendoza

Vilela

Voelz

et al. 2014

Cold Spring Harbor Perspectives in Medicine

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In recent years, we have seen an increase in the number of immunocompromised cohorts as a result of infections and/or medical conditions, which has resulted in an increased incidence of fungal infections. Although rare, the incidence of infections caused by fungi belonging to basal fungal lineages is also continuously increasing. Basal fungal lineages diverged at an early point during the evolution of the fungal lineage, in which, in a simplified four-phylum fungal kingdom, Zygomycota and Chytridiomycota belong to the basal fungi, distinguishing them from Ascomycota and Basidiomycota. Currently there are no known human infections caused by fungi in Chytridiomycota; only Zygomycotan fungi are known to infect humans. Hence, infections caused by zygomycetes have been called zygomycosis, and the term "zygomycosis" is often used as a synonym for "mucormycosis." In the four-phylum fungal kingdom system, Zygomycota is classified mainly based on morphology, including the ability to form coenocytic (aseptated) hyphae and zygospores (sexual spores). In the Zygomycota, there are 10 known orders, two of which, the Mucorales and Entomophthorales, contain species that can infect humans, and the infection has historically been known as zygomyEditors:

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Section: Iron Chelation Therapy and Other Novel Approachesmentioning

confidence: 99%

Human Fungal Pathogens of Mucorales and Entomophthorales

Mendoza

Vilela

Voelz

et al. 2014

Cold Spring Harbor Perspectives in Medicine

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“…This may have been because of the fact that posaconazole showsmodestactivityagainst R.oryzae, the most common species of mucormycosis (Dannaoui et al 2003;Barchiesi et al 2007;Rodriguez et al 2008;Ibrahim et al 2009). However, escalation of posaconazole exposure has shown efficacy, and combination with tacrolimus also showed enhanced effect (Rodriguez et al 2010;Lewis et al 2013). Continued PD study and analyses are important for future investigation to close knowledge gaps related to therapy for mucormycosis and other emerging fungal pathogens.…”

Section: Pk/pd Analysis Of Combination Therapymentioning

confidence: 99%

Antifungal Pharmacokinetics and Pharmacodynamics

Lepak

Andes

2014

Cold Spring Harbor Perspectives in Medicine

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Successful treatment of infectious diseases requires choice of the most suitable antimicrobial agent, comprising consideration of drug pharmacokinetics (PK), including penetration into infection site, pathogen susceptibility, optimal route of drug administration, drug dose, frequency of administration, duration of therapy, and drug toxicity. Antimicrobial pharmacokinetic/pharmacodynamic (PK/PD) studies consider these variables and have been useful in drug development, optimizing dosing regimens, determining susceptibility breakpoints, and limiting toxicity of antifungal therapy. Here the concepts of antifungal PK/PD studies are reviewed, with emphasis on methodology and application. The initial sections of this review focus on principles and methodology. Then the pharmacodynamics of each major antifungal drug class ( polyenes, flucytosine, azoles, and echinocandins) is discussed. Finally, the review discusses novel areas of pharmacodynamic investigation in the study and application of combination therapy. PHARMACOKINETICS

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“…and the Mucorales (12)(13)(14). Our group recently reported that the combination of TCR with PCZ improves control of invasive, necrotizing cutaneous mucormycosis in immunosuppressed mice compared to that achieved with PCZ monotherapy (15). Since calcineurininhibiting agents have been extensively used in humans, it may be possible to manipulate this pathway, in order to develop novel strategies for recalcitrant fungal infections, such as mucormycosis.…”

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confidence: 99%

The Calcineurin Pathway Inhibitor Tacrolimus Enhances the In Vitro Activity of Azoles against Mucorales via Apoptosis

Shirazi

Kontoyiannis

2013

Eukaryot Cell

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The calcineurin pathway regulates antifungal drug resistance and the virulence of several major human-pathogenic fungi, including the recalcitrant Mucorales. We hypothesized that the fungistatic triazoles posaconazole (PCZ) and itraconazole (ICZ) become fungicidal in the setting of the calcineurin inhibitor tacrolimus (TCR) and that such an effect is mediated through apoptosis. Fungicidal activity and apoptosis were studied using standard microbiological techniques and hyphal metabolic and vital dye reduction assays at 37°C in RPMI 1640. Apoptosis was characterized by detecting intracellular Ca 2؉ , phosphatidylserine (PS) externalization, DNA fragmentation, plasma membrane integrity, chromatin condensation, reactive oxygen species (ROS) generation, caspase-like activity, ATP, and cytochrome c release. MICs for PCZ and ICZ alone were significantly higher (8 to 128 g/ml) than those of PCZ or ICZ plus TCR (0.25 to 4 g/ml) for Rhizopus oryzae, Cunninghamella bertholletiae, and Mucor circinelloides. Both PCZ and ICZ in combination with TCR became fungicidal, and their activity was mediated through increased apoptotic cell death of R. oryzae (10 to 50%), C. bertholletiae (5 to 50%), and M. circinelloides (5 to 55%) germlings, with morphological apoptotic changes characterized by externalization of PS, nuclear condensation, and DNA fragmentation. Moreover, activation of the caspase-like activity was correlated with cell death induced by TCR plus PCZ or ICZ. These changes correlated with elevated intracellular Ca 2؉ and ROS levels and disturbance of mitochondrial potential. We found that PCZ or ICZ in combination with TCR renders Mucorales sensitive to triazoles via apoptotic death. These observations could serve as a new paradigm for the development of new therapeutic strategies.

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Tacrolimus Enhances the Potency of Posaconazole Against Rhizopus oryzae In Vitro and in an Experimental Model of Mucormycosis

Abstract: Combination posaconazole-tacrolimus therapy displays synergism in vitro and improved antifungal efficacy in vivo in 2 phylogenetically distinct models of mucormycosis.

Cited by 60 publications

References 41 publications

Human Fungal Pathogens of Mucorales and Entomophthorales

Human Fungal Pathogens of Mucorales and Entomophthorales

Antifungal Pharmacokinetics and Pharmacodynamics

The Calcineurin Pathway Inhibitor Tacrolimus Enhances the In Vitro Activity of Azoles against Mucorales via Apoptosis

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